9-alpha-methyl steroids

ABSTRACT

The compounds are 13-(lower)alkyl-9 Alpha -methyl-gonanes which may be aromatically unsaturated or 4-, or 5(10)-mono-unsaturated, e.g. 3-methoxy-9 Alpha -methylestra-1,3,5(10)-trien-17-one and 17 Beta -acetyl-9 Alpha -methylestra-4-en-3-one. The compounds are useful as pharmaceuticals.

United States atent Coombs et a1.

1 51 Feb. 20, 1973 1541 9-ALPHA-METHYL STEROIDS 3,102,125 8/1963 Kinclet al. ..260/397.4

[75] Inventors: Robert V. Coombs, Chatham; Eu- OTHER PUBuCA-TONS gene E.Galantay, Mornstown, both of NJ. Jones et al. I. Chem. Soc Jour. p.2933-35 (1965) Jones et al., [1 Chem. Soc. Jour. p. 2156-58 (1958) 73 1Asslgnee Sandal wander Inc Hanover N J Beyler et al., Jour. Org. Chem.Vol. 26 p. 2426-28 [22] Filed: July 1, 1971 (1961) [21] Appl No; 159,005Fieser et al. Steroids p. 692-696 (1959) Applezweig Steroid Drugs p. 347(1964) Related US. Application Data [63] Continuation-impart of Ser. No.844,183, July 23, French 1969, Pat. No. 3,655,652, and acontinuation-in-part Attorney-Gerald Sharkm et of Ser. No. 848,705, Aug.8, 1969, abandoned. Cl [5 7] ABSTRACT 52 US. ..260 397. 1 260/239 55 R260/239/ 55 g The compounds are 13-(lower)alkyl-9a-methyl- 260/397326039145; 260/3975, 42'4/241: gonanes which may be aromaticallyunsaturated or 4-,

424/243 or 5( l0)-mono-unsaturated, e.g. 3-methoxy-9a- 51 1m. (:1...C07c 169/32, C07c 169/34 y and i y [58] Field of Search ..lMachineSearched Steroids 9a-methylestra-4-en-3-one. The compounds are useful aspharmaceuticals. [56] References Cited 5 Claims, No Drawings UNITEDSTATES PATENTS 2,977,286 3/1961 Laskin et a1. ..195/51 9-ALPHA-METHYLSTEROIDS This is a continuation-in-part of copending application Ser.No. 844,183 filed July 23,1969 now US. Pat. No. 3,655,652 and ofcopending application Ser. No. 848,705, filed Aug. 8, 1969 nowabandoned.

This invention relates to steroidal compounds, and more particularly to13-alkyl-substituted gonane compounds having a9a-methyl substituent, aswell as to methods of preparing such compounds and to intermediates inthe preparation of such compounds. This invention also relates topharmaceutical compositions containing such compounds and positions.

An embodiment of this invention are gonane compounds which may beconveniently represented by the Formula I:

Compounds I are obtainable by hydrolysis-rearrangement of thecorresponding Compound ll:

"- R cm to the use of said comwherein R is tetrahydropyran-Z-yl,tetrahydrofuran-Z-yl, or lower alkyl, i.e., having from one to fourcarbon atoms, such as methyl, ethyl, propyl or butyl, including theirisomeric forms, but is preferably unbranched.

The above-mentioned hydrolysis-rearrangement is referred to hereinafteras Process 1.

Depending upon whether vigorous acid hydrolysis (step b) of a CompoundII, or mild acid hydrolysis (step 7 a) thereof is employed, either aCompound Ia or a Compound lb will be obtained, In addition, a CompoundIa may be converted'to its corresponding Compound lb (step c); saidreaction steps are further described below.

The above-mentioned preparation of Compounds la and II are convenientlyrepresented by Reaction Scheme A, below, wherein only the A-rings of thecompounds are shown, (as this is the portion of the molecule on whichthe reaction occurs), and R is as defined above:

Referring to the above Reaction Scheme A:

Step a is a mild cleavage, effected, preferably with oxalic acid, aceticacid or generally in acid media with pH value above 2 and preferablybetween 3 and 4; and preferably for a period of less than about 3 hours.

Step b is a more vigorous cleavage, effected, e.g., with oxalic acid orhydrochloric acid, at a pH value lower than that of step a andpreferably between I and 2.

Step c may be carried out under the same conditions.

as are described for step b, or can be effected by prolonged treatmentof a compound lb, e.g., for a period longer than about 3 hours, underthe conditions described for step a.

Any of steps a, b and 0 may be carried out at temperatures from, e.g., 0to 100 C., preferably from 20 to C., if desired in the presence ofsuitable watermiscible inert organic solvent, such as a lower alkanol,e.g. methanol; however, when the acid reactant is liquid it may beemployed in excess to serve as solvent,

e.g., acetic acid. Steps a and b should be, and step c is preferablycarried out in the presence of water.

If desired steps a and 0 may be combined so that a compound II isconverted to its corresponding compound Ib without recovery of anyintermediate compound Ia. I

Alternatively, step may be carried out in a basic medium (step c), e.g.,a compound la may be dissolved in a lower alkanol, such as methanol,ethanol, or the like, employing aqueous sodium hydroxide or potassiumhydroxide solution of from about 0.01 N to 2N, for

from about 1 hour to about 6 hours, e.g. at from 20 to 100, preferablyat reflux, to give the corresponding lb.

A Compound II is obtainable by oxidizing a l7B-( lhydroxyethyl)-substituted analog thereof, i.e. a Compound III. Theoxidation of the l-hydroxyethyl group of a Compound III to an acetylfunction (Process 2) may be carried out employing convention methods ofoxidizing a secondary alcohol to a carbonyl, e.g. using chromiumtrioxide in pyridine or acetone; the Oppenauer Reaction or silvercarbonate in boiling benzene.

A Compound lll is obtainable by reducing an aromatic analog thereof,i.e., a Compound IV. The reduction (Process 3) of the aromatic analog,i.e. having unsaturation at the 1,3 and 5(10) positions, to the 2,5(l0)-diene may be accomplished by employing the so-called Birchreduction, which broadly involves use of an alkali metal, e.g. lithium,in the presence of a proton donor such as a lower alkanol, e.g.t-butanol or ethanol in liquid ammonia at reduced temperatures(sufficient to maintain the ammonia in a liquid state). If desired, asolvent such as an ether, e.g., tetrahydrofuran can be used; however,the ammonia can serve as the reaction medium.

A Compound IV is obtainable by hydrating (Process 4) a17-ethylidine-3-ether-9a-methylestral,3,5()-triene, i.e., a Compound V.The hydration may be effected by use of a hydroboration technique, e.g.by treatmentwith borane followed by treatment with hydrogen peroxideunder basic conditions. The borane reagent may be used as such or in aconvenient form, e.g. as a borane-tetrahydrofuran solution.

A Compound V is obtainable by ethylidenating a Compound VI, i.e. a3-ether-9a-methylestra-l,3,5( l0)- tn'ene-l7-one, with a so-calledWittig reagent, i.e. triphenyl-ethyl-phosphonium ylide (Process 5). TheWittig reagent is prepared by reacting a triphenylethyl-phosphoniumhalide with a strong base, e.g. ethyl-triphenyl-phosphonium iodide withsodium methylsulfinylmethide, in an inert solvent, e.g. dimethylsulfoxide.

Alternatively, Compound lIl may be treated according to Process 1 toobtain an intermediate (Compound CH: H2?

wherein R is as defined above, the dotted lines indicate the presence ofa single double bond at either of positions 4 or 5(10), and Compound Xmay be oxidized (Process 6) at the 17 (l -hydroxyethyl) radical thereofto obtain the corresponding Compound I. The oxidation may be carried outin the same manner as the oxidation described in Process 2.

The preparation of Compounds 11 from Compounds VI by the series ofProcesses 2, 3, 4 and 5 is conveniently represented by Reaction SchemeB, below, wherein R and R are as defined above.

REACTION SCHEME B on, R 0 3 l Process 5 (ethylidcnation") l Process 3(reduction) III 1'1 (III-1' H20 CHOH l CF13 I m l Process 2 (oxidation)II R CH If desired a Compound ill or a Compound X which has unsaturationat the 5(l0)-position, i.e. a Compound Xa, may be oxidized under acidicconditions to obtain a corresponding Compound lb. Where a Compound Xa isused, the acidic conditions may be those employed in step c of Process1, with or without water being present. Where a Compound [11 is used theacidic conditions may be those employed in step b of Process 1. Chromiumtrioxide in concentrated sulfuric acid, or acetic acid is particularlyuseful in such reaction.

As will be appreciated, in oxidizing a Compound Xa to the correspondingCompound Ia, acidic conditions which would cause rearrangement, shouldbe avoided, as such can result in formation of a Compound Ib.Accordingly, chromium trioxide in pyridine is particularly useful asoxidizing agent in such reaction.

Compounds VI used in Process 5 may be conveniently obtained startingfrom Compounds A below by a series of steps, comprising Process 7'.Process 7, is represented in Reaction Scheme C, below, wherein R and Rare as defined above and n is 1 or 2.

REACTION SCHEME C PROCESS 7 (g k Dn H2 HOTA j HO- (A) l Stop a(3etherlfication) R E k Qn H; K HO 0 l Step b (ll-oxidation) R o cH Hz 2n 0 i Step 0 (C-mcthylatlon) R H A 2)n O 2 0 l Step (1 (carbonylreductlon) ventional for the etherification of a phenolic hydroxyfunction. Thus, where R is alkyl, the alkylating agent Step e (17-ketalcleavage) may, for example, be an alkyl iodide having from one to fourcarbon atoms, and the process conveniently carried out under basicconditions, provided, for example, by the presence of anhydrouspotassium carbonate. Suitably, the process is carried out in an inertorganic solvent, for example a lower alcohol such as methanol. Thereaction temperature may for example be from 60 to C., althoughpreferably the reaction is performed at the reflux temperature of thereaction medium. When an alcohol is used as solvent, it is preferredthat the alkyl moities of the alcohol and the alkylating agent be thesame. Compounds B where R is tetrahydropyranyl or tetrahydrofuranyl,such may be obtained in a conventional manner, e.g. by reacting aCompound A with dihydropyran or dihydrofuran in the presence of anacidic catalyst, such as p-toluene sulfonic acid or phosphorusoxychloride.

Compounds A are either known and may be prepared by methods described inthe literature or where not known may be prepared by known means fromknown starting materials.

In step b, a Compound B, e.g. an l7-ethylenedioxy-3-etherified-9a-methylestra-l ,3 ,5 l0)-1 lfi-hydroxytriene is oxidized toconvert the ll-hydroxy position thereof to a carbonyl function. Theoxidation of a secondary alkyl hydroxy function to a carbonyl function,may be carried out by conventional methods, e.g. by the so-called Moffatoxidation.

Step c, i.e. the C-me thylation to obtain e.g. a 17-ethylene-dioxy-3-etherified-9a-methylestra-1,3 ,5( l0 trien-l l-one, maybe carried out by reacting a Compound C with a methylating agent in thepresence of a strong base at a temperature of from about l 0 to 60 C.,in a suitable solvent.

The methylating agent, of Step c, i.e. a Compound Q may be representedby the formula:

wherein Z is a nucleofugal leaving group, i.e. the acid residue of amineral acid, other than fluorine, e.g. a

halogen atom having an atomic weight of from 35 to 127, or the acidresidue of an organic sulfonic M is a alkali metal, e.g. Na or K.

Step c should be carried out in a suitable solvent, e.g. t-butanol ordimethyl sulfoxide; however, where the methylating agent is liquid underthe reaction conditions, excess methylating agent may serve as solvent.

It is preferred to employ the methylating agent in excess, particularlyin such a large excess that it serves as solvent, i.e. reaction medium,e.g. of the order of from about to 200 fold excess. Z is preferablyiodide and MA is preferably potassium t-butoxide.

Reaction conditions conventionally applied to C- methylation reactionsare therefore applied, e.g. it is preferred to carry out the reaction inan inert gas atmosphere, e.g. under dry nitrogen.

In step d, a Compound D is reduced to its corresponding Compound E, i.e.the carbonyl function at the ll-position is converted to a methyleneunit, by means conventionally employed for reducing a carbonyl to amethylene structure, e.g. the well-known Wolff- Kishner reduction.

In step e, the ketal function at the l7-position of a Compound E is thenacid cleaved to yield the corresponding Compound VI, e.g. a3-etherified-9amethylestra-l ,3,5(lO)-trien-l7-one. Step e may becarried out in the conventional manner for cleaving a ketal linkage,e.g. by refluxing with hydrochloric acid or ptoluene sulfonic acid inmethanol.

It will be appreciated that the cleavage step e, if R is atetrahydropyranyl or tetrahydrofuranyl function, may yield a3-hydroxy-analog of :1 Compound VI, i.e. a Compound Vla. Hereinafter theterm Compounds VI includes Compounds VI and their 3-hydroxy analogs(Vla), i.e. R of Compounds VI is replaced in Compounds VI with R whichrepresents a hydrogen atom or R. Accordingly, where a Compound VI isdesired where R is either a tetrahydropyranyl or tetrahydrofuranylfunction, such groups can be introduced onto the 3-position of aCompound Vla by a conventional etherification technique such as isdescribed above in connection with step a of Process 7.

It will also be appreciated that in the above described A they possesspharmacological properties in animals. In

particular, Compounds I have progestational activity and are useful asfertility control agents in war blooded animals, e.g.mammals, and inregulating estrus or menstrual function. The progestational activity ofsaid compounds is indicated by the well-known Clauberg test involvingobservation of uterine changes in immature female white rabbits.

For the above-mentioned uses Compounds I may be combined with apharmaceutically acceptable carrier or adjuvant. They may beadministered orally or parenterally. The dosage will vary depending uponthe mode of administration utilized and the particular compoundemployed. However, in general, satisfactory results are obtained whenthe compounds are administered at a daily dosage of from about 0.0lmilligram to 30 milligrams. This daily dosage may be given in a singledose or divided doses, e.g. two times a day, or in sustained releaseform, independent of body weight. Dosage forms suitable for internaladministration comprise from about 0.005 milligrams to about 30milligrams of the compound in admixture with a solid or liquidpharmaceutical carrier or diluent.

The Compounds VI in addition to their use as intermediates as describedabove, possess pharmacological activity in animals. In particular,Compounds V! have estrogenic activity, as indicated by observingincrease in white mouse uterine weight, e.g. as described inEndocrinology 65, 265 (1959). The compounds are therefore useful asestrogenic agents, e.g. in fertility control and estrogen replacementtherapy. These compounds may be combined with a pharmaceuticallyacceptable carrier or adjuvant. They may be administered orally orparenterally. The dosage will vary depending upon the mode ofadministration utilized and the particular compound employed. However,in general, satisfactory results are obtained when the compounds areadministered at a daily dosage of from about 0.3 milligram to 30milligrams. This daily dosage may be given in a single dose or divideddoses, e.g. two timesa day, or in sustained release form, independent ofbody weight. Dosage forms suitable for internal administration comprisefrom about 0.15 milligrams to about 30 milligrams of the compound inadmixture with a solid or liquid pharmaceutical carrier or diluent.

Compounds D also possess estrogenic activity, and may therefore be usedfor the same uses and administered in the same manner as described abovefor Compounds VI, except that daily dosages should be from 1 milligramto 30 milligrams. v

A representative formulation suitable for oral administration is atablet prepared by standard tabletting techniques which contains thefollowing:

Parts by Ingredient Weight 3-methoxy-9a-methylestra-' l,3,5(l0)-trien-l7-one 0.5 Tragacanth 2 Lactone 89 Corn Starch 5 Talcum 3Magnesium Stearate 0.5

The following examples are provided as illustrative of the presentinvention. However, it is to be understood that the examples are for thepurposes of illustration only and are not intended as in any waylimiting the scope of the invention. In the examples all temperaturesare Centigrade and room temperature is 25, un-v less indicatedotherwise.

EXAMPLE 1' 17B-Acetyl-9a-methylestra-4-en 3-one C113 HsC 43:0

This Example illustrates the preparation of a Compound la and Compoundlb. STEP A: l7-Ethylenedioxy-l lB-hydroxy-3-methoxyestra-l ,3,5(l)-triene(Compound B by Process 7, step a) CIIaO A mixture of 15 g of17-ethylenedioxyestra-l,3,5(l0 trien-3,l lB-diol and 30 g of anhydrouspotassium carbonate in 75 ml of methanol and 60 ml of methyl iodide isstirred and heated under reflux for 3 hours. The mixture is then cooledand diluted by addition of 200 ml of water. The methanol and methyliodide are removed by distillation under reduced pressure and theaqueous residue is extracted twice with methylene chloride. The combinedorganic extracts are washed with saturated sodium chloride solution anddried over sodium sulfate. Removal of the solvent gives a residue whichis crystallized from ether to yield l7-ethylenedioxy-l lB-hydroxy-3-methoxyestra-l ,3 ,5( l0)-triene, m.p. l25126C. STEP B:l7-Ethylenedioxy-3-methoxyestra-l,3,5( l0)- triene-l l-one (Compound Cby Process 7, step b) To a stirred solution of 5.13 g ofl7-ethylenedioxyl 1B-hydroxy-3-methoxyestra-l,3,5( l0)-triene in 25 mlof dimethylsulfoxideand 25 ml of benzene is added 3 ml of pyridine and9.3 g of N,N-dicyclohexylcarbodiimide. This mixture is then cooled and1.5 ml of dichloroacetic acid is added. The whole is next stirred atroom temperature for l 1% hours. It is diluted by the addition of 50 mlof ether and a solution of 4 g of oxalic acid in ml of methanol is addeddropwise. The resulting suspension is stirred for 40 minutes at roomtemperature and then filtered. The filtrate is concentrated to drynessand distributed between methylene chloride and a 10 percent aqueoussolution of sodium bicarbonate. The organic phase is washed with waterand dried (Na SO before being evaporated to dryness under reducedpressure. The residue is placed on a column of silica-gel and elutedwith chloroform containing various percentages of methanol. Thefractions eluted with chloroform containing 5 percent of methanol arecombined and evaporated to yield a residue which is crystallized fromhexane/ether (121). Thus is obtainedl7-ethylenedioxy-3-methoxyestral,3,5( lO)-trien-l l-one, m.p. l22l23C.STEP C: l7-Ethylenedioxy-3-methoxy-9a-methylestra- 1,3,5(l0)-trien-ll-one(Compound D by Process 7, step c) To a stirred, ice cooled solutionof 10.5 g of l7- ethylenedioxy-3-methoxyestra-l ,3,5( lO)-trien-l [-onein 300 ml of methyl iodide under an atmosphere of nitrogen is added,over 10 minutes, I20 ml of a 1.1 molar solution of potassiumtert.-butoxide in t-butyl alcohol. The temperature is allowed to rise toroom temperature and the mixture is then stirred for 18 hours. It isnext poured onto 500 ml of water and extracted with methylene chloride,twice. The combined organic extracts are washed with water and driedover sodium sulfate. Removal of the solvent gives an oil which iscrystallized from ether to yield l7-ethylenedioxy-3-methoxy-Qa-methylestra-l ,3,5( l0)-trien-l l-one, m.p. l42l45C.

STEP D: l7-Ethylenedioxy-3-methoxy-9a-methylestral,3,5( l0)-triene(Compound E by Process 7, step d) CHQO A mixture of 534 mg of17-ethylenedioxy-3-methoxy-9a-methylestra-l ,3,5( l0)-trien-l l-one, l gof hydrazine dihydrochloride and 5 g of hydrazine hydrate in 35 g oftriethylene glycol is heated to a temperature of 130 and maintainedthere for 2 1% hours. After this time, 1.8 g of potassium hydroxidepellet is added and the temperature raised to 210. This temperature isalso maintained for 2 hours whilst a mixture of hydrazine and water isslowly allowed to distill out. The reaction mixture is cooled anddiluted with water affording a precipitate which is collected byfiltration. The solid is dissolved in methylene chloride and the organicsolution is dried over sodium sulfate. Removal of the solvent leaves aresidue which is crystallized from hexaneether to yieldl7-ethylenedioxy-3methoxy-9amethylestra-l,3,5(10)-triene, mp. C.

STEP E: 3-Methoxy-9a-methylestra-l ,3,5( l0)-trien-l7 -one (Compound VIby Process 7, step e) CHJO are isolated by filtration. The crystallinesolid is washed with a small quantity of ether to yield3-methoxy-9amethylestra-l,3-5(10)-trien-17-one, m.p. 190-192C. STEP F:l'l-Ethylidene-3-methoxy-9a-methylestra- 1,3,5()-triene (Compound V byProcess 5) 5 CHaO To a (25) solution of sodium methylsulfinylmethide,prepared in the usual way from 2.4 g of sodium hydride in 45 ml ofdimethyl sulfoxide, there is rapidly added a solution of 22.4 g ofethyltriphenylphosphonium iodide in 90 ml of dimethyl sulfoxide. To theresulting deep red mixture, 4.0 g of 3-methoxy-9a-methylestra- 1,3,5(l0)-trien-17-one is added and kept at 60 for 18 hours. After pouring onice (200 g) the product is extracted with petroleum ether and purifiedby filtration of the petroleum ether solution through 13 g of alumina(Grade I). I STEP G: 17B-(1'-Hydroxyethy1)-3-methoxy-9amethylestra-l,3,5(10)-triene(Compound IV byProcess 4) IIOH HOH

HaC

To a solution of 3.6 g of 17B-(l'-hydroxyethyl)-3-methoxy-9a-methylestra-1,3,5(10)-triene in a refluxing (30) mixture of100 ml of liquid ammonia, 30 ml of tetrahydrofuran and 20 ml of tertiarybutanol, there is added in small pieces 0.8 g of lithium metal and theresulting mixture held for 3 hours at about 30. 30 ml ('10)-diene(Compound 11 by Process 2) To a mixture of 260 mg of chromium trioxidein 10 ml of pyridine, 302 mg of 17B-( l'hydroxyethyl)-3-methoxy-9a-methylestra-2,5(l0)-diene is added and kept 18 hours at 25.ice is added and the product extracted with benzene; the benzenesolutions are filtered through a short column (10g) of alumina Grade1-11), evaporated to dryness, and the product crystallized fromacetone-hexane (1:1).

STEP J: 17B-Acetyl-9a-methylestra-5(10)-en-3-one (by Process 1, step a)A solution of 1 g of l7B-acetyl-3-methoxy-9amethylestra-2,S(10)-diene inml of methanol is admixed with a solution of 1 g of oxalic acid in 20 mlof water and the resulting mixture is kept at 50 for 30 minutes.Following this reaction period, the mixture is concentrated in vacuo toabout 20 ml then poured into ice water. The resulting precipitate iscollected by filtration, washed with water until neutral then dried.

Recrystallization of the dry precipitate from acetonehexane( 1:1 gives17B-acetyl-9a-methylestra-5( i0)- en-3-one.

Step K: l7B-Acetyl-9oz-methylestra-4-en-3-one (by Process 1,step c) Asolution of 1.0 g of 17B-acetyl-9a-methylestra- 5( l0)-en-3-oneobtainable as described in step j, above in 80 ml of methanol is heated,at 40, with 5 ml of 5 N aqueous hydrochloric acid. After 30 minutes, icewater and 1.0 g of sodium acetate is added, the resulting precipitate isfiltered, washed and dried. Recrystallization from methylenedichloride-ether gives 17B-acetyl- 9a-methylestra-4-en-3-one.

By replacing the 17-ethy1enedioxyestra-1,3,5(10)- triene-3,'11B-diolused in step a of this example with an approximately equivalent amountof l3-ethyl-l7- ethylenedioxygona-i,3,5(10)-triene-3,1IB-diol or 13-propyl-l7-ethylenedioxygona-1,3,5(10)-triene-3,1 1B- diol, and followingthe procedures of steps a to i of this example there is obtained17B-acetyl-l3-ethyl-3- methoxy-9a-methylgona-2,5(l0)-diene or17(3-acetyll3-propyl-3-methoxy-9a-methylgona-2 ,5( 10 )-diene, which bytreatment according to step j yields 17B-acetyl-i3-ethyl-9a-methylgona-5(10)-en-3-one or17B-acetyl-13-propyl-9a-methylgona-5( 10)-en-3-one respectively.Vigorous acid hydrolysis of the 173- acetyl-l3ethyl-9a-methylgona-2,5(l0)-diene or 178- acetyll 3-propyl-9a-methylgona-2,5( 10 )-dieneaccording to the procedure of step It yields 17B-acetyl-13-'ethyl-)a-methylgona-4-en-3-one or l'IB-acetyl-IB-propyl-Qa-methylgona-4-en-3-one, respectively.

Following the procedure of step a of this example, but using anapproximately equivalent amount of ethanol and ethyl iodine in place ofthe methanol and methyl iodine used therein, there is obtained 17-ethylenedioxy-3 -ethoxy-l lfi-hydroxyestra-l ,3 ,5 l

triene, which upon treatment as described in steps b to i of thisexample yields l7B-acetyl-3-ethoxy-9amethylestra-2,5(l0)-diene.Treatment of this product according to the procedure of step j yieldsl7B-acetyl-9 a-methylestra-(10)-en-3-one. Vigorous acid hydrolysis ofl7fi-acetyl-3-ethoxy-9a-methylestra-2,5( l0)- diene according to theprocedure of step k yields 17B- acetyl-9a-methylestra-4-en-3-one.

EXAMPLE 2 EXAMPLE 3 17B-Acetyl-9a-methylestra-4-en-3-one Repeating theprocedure described in Step K of Example 1, except replacing thel7B-acetyl-9a-methylestta-5( l0)-en-3-one used therein with anapproximately equivalent amount of17B-acetyl-3-methoxy-9amethylestra-2,5(l0)-diene, obtainable as theproduct of Step I in Example 1, there is obtainedl7B-acetyl-9amethylestra-4-en-3-one.

By repeating the procedure of Step K of Example 1, but replacing thel7B-acetyl-9a-methylestra-5(10)-en- 3-one used therein with andapproximately equivalent amount of 17B-( 1'-hydroxyethyl)-3-methoxy-9amethylestra-2,5(l0)-diene, obtainable as theproduct of Step H of Example 1, there is obtained 17-( lhydroxyethyl)-9a-methylestra-4-en-3-one which by treatment according tothe procedure of Step I of Example l, yieldsl7B-acetyl-9a-methylestra-4-en-3-one.

EXAMPLE 4 l7fl-Acetyl-9a-methylestra-4-en-3-one To 2.7 gof l7B-( l'-hydroxyethyl)-9a-methylestra-4- en-3-one, (obtainable as described inExample 3, above), in 70 ml of dimethylforamide (D.M.F.), there is added2.7 g of chromium trioxide under cooling, followed by 50 ml of D.M.F.containing 2 ml of concentrated sulphuric acid. The resulting dark redmixture is allowed to stand at room temperature for 2 hours after whichit is shaken out with a water/ether mixture. The ether phase is thenwashed with saturated sodium bicarbonate solution. The ether extract isthen dried over sodium sulphate, after which it is evaporated to obtainthe title product as a yellow oil which is then crystallized fromether/methylene chloride (5:1).

By repeating the procedure of this example, but replacing thel7B-(l-hydroxethyl)-9a-methylestra-4- en-3-one used therein with anequivalent amount of 17 l'-h drox eth l -3- th -9 -meth lestra- 2,( l0)-di ene, the ie is o t nei l l7 -acetyl-9amethylestra-4-en-3-one.

By repeating the procedure of Step J of Example I,

but replacing the l7B-acetyl-3-methoxy-9a-methylestra2,5(10-diene usedtherein with an approximately equivalent amount of l7B-( l'-hydroxyethyl)-3- methoxy-9a-methylestra-2,5(l0)-diene (obtainable byStep H of Example 1), there is obtained 17fi-( lhydroxyethyl)-9a-methylestra-5( l0-en-3-one, which by treatmentaccording to the procedure of this example yieldsl7B-acetyl-9a-methylestra-4-en-3-one. When 17 B-( l'-hydroxyethyl)-9a-methylestra-5( 10)- en-3-one is treated in accordancewith the procedure of step i, there is obtainedl7B-acetyl-9a-methylestra- 5(10)-en-3-one.

What is claimed is:

1. A compound of the formula:

wherein R is a hydrogen atom or alkyl having one to two carbon atoms;and ring A is:

wherein R is tetrahydropyran-Z-yl, tetrahydrofuran-Z- yl, or alkylhaving from one to four carbon atoms.

2. The compound of claim 1 which is l7fi-(l hydroxyethyl)-3-methoxy-9a-methylestra-Z ,5 10)- diene.

3. A compound of the formula:

bon atoms; and

R is tetrahydropyran-Z-yl, tetrahydrofuran-2-yl, or

alkyl having from one to four carbon atoms.

4. A compound of claim 3 which is l7-ethylidene-3-methoxy-9a-methylestra-l ,3 ,5( l0)-triene.

5. The compound of claim 1 which is l7B-( lhydroxyethyl)-3-methoxy-9a-methylestra-l ,3 ,5( l0)- triene.

# i i i

1. A compound Of the formula: wherein R is a hydrogen atom or alkylhaving one to two carbon atoms; and ring A is: wherein R1 istetrahydropyran-2-yl, tetrahydrofuran-2-yl, or alkyl having from one tofour carbon atoms.
 2. The compound of claim 1 which is 17 Beta-(1''-hydroxyethyl)-3-methoxy-9 Alpha -methylestra-2,5(10)-diene.
 3. Acompound of the formula: wherein R is a hydrogen atom or alkyl havingone to two carbon atoms; and R1 is tetrahydropyran-2-yl,tetrahydrofuran-2-yl, or alkyl having from one to four carbon atoms. 4.A compound of claim 3 which is 17-ethylidene-3-methoxy-9 Alpha-methylestra-1,3,5(10)-triene.